TRANSPLANTATION: How to identify liver transplant recipients who no longer need drugs

A very small number of individuals who have had a liver transplant are able to stop taking drugs that prevent the immune system from attacking their transplanted liver (immunosuppressants). These people are said to be tolerant of their new liver, and becoming independent of immunosuppressants revolutionizes their life, as long-term use of immunosuppressants has serious side-effects. The problem is, there is no diagnostic test to identify these people. However, Alberto Sánchez-Fueyo and colleagues, at Hospital Clínic Barcelona, Spain, have now made a step toward this goal by identifying several gene signatures that distinguish tolerant liver transplant recipients from those that are not tolerant. Importantly, these gene signatures could be detected by analyzing the peripheral blood and did not require an invasive procedure. Vicki Seyfert-Margolis and Laurence Turka discuss the immense clinical importance of this study in an accompanying commentary.

TITLE: Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients

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CARDIOVASCULAR DISEASE: Early warning system: a new way to detect the cause of heart attack

One of the most common causes of heart attacks (also known as myocardial infarctions) and stroke is atherosclerosis, a disease of the major arterial blood vessels. Heart attacks and stroke occur when atherosclerotic plaques in the wall of an artery (which are what gives the disease its alternative name of hardening of the arteries) rupture, clogging up the blood supply to the heart or brain, respectively. A new, noninvasive way to detect the presence of ruptured atherosclerotic plaques has been developed by Kitty Cleutjens and colleagues, at the University of Maastricht, The Netherlands.

Specifically, it was shown that the blood of individuals with ruptured atherosclerotic plaques (as evidenced by hospitalization for an acute heart attack) contained antibodies reactive against two newly identified peptides, E1 and E12. The presence of these antibodies was detected extremely early after the onset of symptoms of a heart attack and so the authors hope that this approach might one day be used to improve early detection of ruptured atherosclerotic plaques such that individuals can get more timely treatment. However, as they note, further studies on additional patients are needed before this work can be translated into the clinic, and this sentiment is echoed, in an accompanying commentary, by Robert Gerszten and colleagues, at Massachusetts General Hospital, Charlestown.

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HEMATOLOGY: Solving problems with platelets

Individuals with very few platelets (the blood cells that regulate blood clot formation) are said to suffer from thrombocytopenia. There are many causes of thrombocytopenia, including increased destruction of platelets. New data, generated by two independent groups, have provided clinically relevant insight into two forms of thrombocytopenia caused by increased platelet destruction - immune thrombocytopenic purpura (ITP) and fetomaternal alloimmune thrombocytopenia (FMAIT). The importance of these studies for the development of new therapeutics is discussed in an accompany commentary by Bethan Psaila and James Bussel, at Weill Cornell Medical College of Cornell University, New York.

In the first study, Masataka Kuwana and colleagues, at Keio University School of Medicine, Japan, set out to understand why platelet numbers return to nearly normal levels in about 50% of individuals with ITP who are also infected with the bacterium Helicobacter pylori after they have been treated with antibiotics to clear their H. pylori infection. It was found that immune cells known as monocytes (which are involved in the destruction of platelets through their ability to take up and degrade antibody coated platelets via activating Fc receptors) exhibited characteristics of activated cells before the H. pylori infection was eradicated. This included high levels of activating Fc-gamma receptors and low levels of an inhibitory Fc-gamma receptor. Upon H. pylori eradication levels of the activating Fc-gamma receptors decreased and levels of the inhibitory receptor increased. The authors therefore conclude that H. pylori eradication dampens the activation status of monocytes such that their Fc-gamma repertoire favors uptake and destruction of platelets and that this is reversed upon H. pylori eradication.

In the second study, Cedric Ghevaert and colleagues, at NHS Blood and Transplant, United Kingdom, developed an approach to manipulate the interaction between antibody coated platelets and activating Fc-gamma receptors to decrease monocyte uptake and destruction of platelets. In FMAIT, mothers generate antibodies that bind to a molecule (HPA-1a) on the platelets of their fetus such that they are taken up by monocytes and destroyed. The authors developed a molecule that binds HPA-1a in place of the mother's antibodies when analyzed in vitro. Further in vitro and mouse studies indicated that this molecule dramatically decreased platelet destruction, leading to the suggestion that this approach be evaluated in human clinical studies.

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OPHTHALMOLOGY: How to PROM(1)ote vision

Age-related macular degeneration is the leading cause of central vision loss in Americans over the age of 65. Inherited forms of macular degeneration are far less common, but, as noted in a commentary by Mark Kleinman and Jayakrishna Ambati, at the University of Kentucky, Lexington, defining the genes mutated in individuals with these forms of the disease has led to numerous discoveries regarding the molecular bases of vision. This has again proven true in work performed by a team of researchers, at the University of Utah, Salt Lake City, and the University of California, at Los Angeles, that has determined why a genetic mutation that leads to the generation of a mutant form of the protein PROM1 causes macular degeneration.

In the study, the same mutant form of PROM1 was identified in individuals with three different forms of inherited macular degeneration. When mice were engineered to express this mutant form of human PROM1 it was observed that cells in the eye crucial for vision (rod photoreceptors) underwent progressive degeneration. Further, the part of the rod photoreceptors known as the outer segment, which is made of a series of discrete membranous disks and is the light-sensing part of the cell, was greatly overgrown and misoriented. These data indicate that PROM1 seems to direct the organization of rod photoreceptor outer segment disks, providing important insight into the mechanisms underlying vision.

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METABOLISM: Improving the efficacy of enzyme replacement therapies

Mucopolysaccharidoses (MPSs) are a family of genetic diseases caused by deficiency in any one of a number of proteins known as enzymes. The tissues of individuals with MPSs accumulate high levels of molecules known as GAGs, ultimately resulting in premature death. Certain tissues are resistant to administration of the deficient enzyme (enzyme replacement therapy [ERT]), possibly due, in part, to the body's immune response to the replaced enzyme. In a new study, a team of researchers, at the University of California, Los Angeles, the University of Tennessee, Knoxville, and BioMarin Pharmaceutical Inc., Novato, used dogs with a disease similar to MPS I to demonstrate that treatments that make the immune system tolerate the replaced enzyme (i.e., make the immune system think that the replaced enzyme is a normal part of the body that should not be attacked) improves the effectiveness of ERT.

Dogs with a disease similar to MPS I that had not been "tolerized" to the missing enzyme developed antibodies against the replacement enzyme and showed a less favorable response to ERT than the tolerized dogs, where ERT reduced GAG accumulation. The authors conclude that inducing immune tolerance to replacement enzymes could improve the success of ERT for MPS I as well as other MPSs in humans. In an accompanying commentary, Katherine Ponder of Washington University School of Medicine, St. Louis, agrees with this conclusion and further suggests that similar immune tolerance or immunosuppressive treatments are likely to become standard practice for treating individuals with MPSs or related disorders.

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METABOLIC DISEASE: The protein FSP27 helps bulk up white fat

White fat cells (adipocytes) contain a large droplet of fat-soluble molecules (lipids) that acts as an energy store that can be built up or used as necessary, to balance energy intake and expenditure. Obesity, which occurs when an individual's energy intake is greater than their expenditure, is associated with complications such as type 2 diabetes, and it is hoped that understanding the mechanism(s) by which these lipid droplets form and are maintained might provide clues about how obesity leads to such severe consequences. And now, Masato Kasuga and his colleagues, at Kobe University Graduate School of Medicine, Japan, have revealed a link between lipid accumulation in white adipocytes, energy balance, and a characteristic of type 2 diabetes, resistance to the effects of the hormone insulin.

In the study, the protein FSP27 was found to be localized to lipid droplets in mouse white adipocytes and to enhance the formation of white adipocytes from precursor cells. Mice deficient in FSP27 were protected from obesity and insulin resistance, and had an increased metabolic rate (i.e., they burnt more energy). FSP27 depletion in cultured mouse white adipocytes resulted in the breakdown of lipids, whereas FSP27 overexpression promoted lipid droplet formation. The authors therefore conclude that FSP27 promotes the formation of lipid droplets in white adipocytes and thereby has a crucial role in trying to control the energy imbalance that arises in obesity. The importance of these data and the next steps forward are discussed in an accompanying commentary, by Vishwajeet Puri and Michael Czech, at the University of Massachusetts Medical School, Worcester.